CN107056785A - It is used as the heterocyclic compound of IDO and TDO inhibitor - Google Patents

It is used as the heterocyclic compound of IDO and TDO inhibitor Download PDF

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CN107056785A
CN107056785A CN201610893887.0A CN201610893887A CN107056785A CN 107056785 A CN107056785 A CN 107056785A CN 201610893887 A CN201610893887 A CN 201610893887A CN 107056785 A CN107056785 A CN 107056785A
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cycloalkyl
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CN107056785B (en
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张汉承
刘世峰
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Hangzhou Emtronix Medical Technology Co Ltd
Hangzhou Innogate Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

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Abstract

The invention provides the heterocyclic compound as IDO and TDO inhibitor, specifically the invention provides a class novel heterocyclic compounds, it synthesizes and is used as the application of IDO inhibitor and TDO inhibitor.Treatment and IDO1 and/or TDO activity related diseases can be used for according to the heterocyclic compound as IDO and TDO inhibitor of the present invention.

Description

It is used as the heterocyclic compound of IDO and TDO inhibitor
Technical field
The invention belongs to field of medicaments, specifically the invention provides a class novel heterocyclic compounds, it is synthesized and conduct The application of IDO inhibitor and TDO inhibitor.
Background technology
Indole amine 2,3-dioxygenase (indoleamine 2,3-dioxygenase, IDO) and tryptophan 2,3- oxygenases (tryptophan 2,3-dioxygenase TDO) is that tryptophan is catalytically decomposed to reduce limit containing ferrous oxidation for kynurenin Fast enzyme.IDO has two kinds of isomers (IDO1, IDO2), and extensive height is expressed in various kinds of cell, and row are such as：God Through member, astroglia, microglia cell, particularly antigen presenting cell (macrophage and dendritic cells). Expressions of the IDO in human normal cell is relatively low, but when body is in infection, inflammation, in lipopolysaccharides (LPS), IFN- Its expression can substantially increase in the presence of the cell factors such as γ.IDO high expression phenomenons present in kinds of tumors tissue, Confirm that the immune tolerance of IDO and malignant tumour is closely related.IDO may suppress the immune anti-of local T cell by three kinds of mechanism Should：1. tryptophan depletion mechanism, tryptophan is the essential amino acid in T cell activation hyperplastic process, excessive in tumour cell IDO Deficiency of tryptophan can be caused after expression, IDO inhibitor can make T cell Proliferation Ability be restored；2. tryptophan metabolite Toxic mechanism, the metabolite (L- kynurenins and pyridine carboxylic acid) of tryptophan can directly suppress T cell propagation and can induce It is dead；3. regulatory T cells (Tregs) can suppress T cell propagation growth, the IDO of overexpression can be by inducing Tregs Propagation come suppress activation T cell, so as to be created favorable conditions for the invasion and attack and transfer of tumour cell.Therefore indoleamine 2,3- Dioxygenase is likely to become a kind of effective target spot in tumour immunity field.Tryptophan 2,3- oxygenases are mainly expressed in liver group In knitting, the tryptophan levels of main responsible regulating system can decompose tryptophan excessive in food, blood is maintained in certain limit The concentration of clear tryptophan and its activity is not adjusted by immune system.Recent research result indicate that transfection TDO people's cell Tryptophan depletion can be made to prevent T lymphopoiesis, TDO may can adjust the immune resistance to of tumour as IDO1 By, therefore suppression TDO is likely to become a kind of effective oncotherapy means.
Increasing research shows that small molecule IDO inhibitor can be used for the treatment of a variety of diseases, and such as, virus causes row Infectious disease, such as HIV, HPV, disease caused by the virus such as HCV；It is the nervous system disease, such as depression, Alzheimer disease, multiple Property sclerosis, parkinsonism, Huntingdon disease etc.；Various cancers, lung cancer, carcinoma of urinary bladder, breast cancer, kidney, stomach cancer, liver Cancer, oophoroma, prostate cancer, cervical carcinoma, intestinal cancer, cell carcinoma, Huppert's disease, cancer of pancreas, lymthoma, leukaemia Deng atherosclerosis, inflammation, pain etc..
IDO inhibitor not only can be used alone, more can be with other targeted drugs, chemotherapeutics or immune formulation (PD- 1, CTLA-4, PD-L1 etc.) drug combination, have broad application prospects.
The content of the invention
It is an object of the invention to provide the novel IDO inhibitor of a class formation and TDO inhibitor, and their preparation side Method and application.
Compound of the first aspect of the present invention there is provided one kind as shown in formula (I), or its pharmaceutically acceptable salt, Prodrug, deuterated derivative, hydrate or solvate：
In formula (I)：
Ring A is 5- member aromatic rings, and wherein each T and U is each independently N or C；Each P, V and W be each independently N or CR3；
Ring B is 5- members or 6- member aromatic rings, and wherein each D, E and F is each independently CR4=CR5、CR4, N, O, S or NR6；
Z is CR8Or N；
R1And R2It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are miscellaneous to 8- members Ring group ,-CN ,-OR9Or-N (R9)2；
Or R1And R2Coupled carbon atom is collectively forming optionally containing the 0-2 hetero atoms for being independently selected from N, O or S 3- to 8- yuan of rings；
M and n are each independently 0,1,2,3 or 4；
Each R3It independently is hydrogen, halogen or C1-4Alkyl；
Each R4And R5It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- Circle heterocycles base, aryl, heteroaryl, cyano group, nitro ,-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O)N(R9)2、-C(O)R9、-S (O)2R9、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9Or-N (R9)C(O)N (R9)2；
Each R6It independently is hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles base, virtue Base, heteroaryl ,-C (O) R9、-C(O)OR9、-C(O)N(R9)2Or-S (O)2R9；
Each R8It independently is hydrogen, halogen or C1-4Alkyl；
Each R9It is each independently hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles Base, aryl, heteroaryl, C3-8Cycloalkyl C1-4Alkyl, 3- are to 8- circle heterocycles bases C1-4Alkyl, aryl C1-4Alkyl or heteroaryl C1-4 Alkyl；
Or in N (R9)2In structure, two R9Coupled nitrogen-atoms is collectively forming 3- to 8- yuan of rings, the 3- to 8- Yuan of rings optionally also are independently selected from N, O or S hetero atoms containing 0-2, and the 3- is optionally taken by=O to 8- yuan of rings Generation；
R is RA、-ORA、-N(RA)(RC)、-C(O)RA、-C(O)N(RA)(RC)、-C(ORB)(RA)(RC)、-C(NHRB)(RA) (RC) ,-C (=N-ORC)RAOr-N (ORC)(RA), wherein,
Each RAIt independently is C6-12Bridge-type bicyclic alkyl (C6-12Bridged bicycloalkyl) or C4-11Contain 1-3 Individual heteroatomic 6- is to 12- member bridge-type bicyclic heterocycles base (Bridged bicyclic heterocyclyl)；Each hetero atom is independent Ground is selected from N, O or S,
Wherein, RAOptionally there is 1-3 RA1Substituted radical and/or optionally there is 1-2=RA2Substituted radical；
Each RA1It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, aryl, heteroaryl, C3-8Cycloalkanes Base, C3-8Cycloalkenyl group, 3- are to 8- circle heterocycles base, cyano group, nitro, N- oxides ,-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O) N(R9)2、-C(O)N(OH)R9、-C(O)R9、-C(NR9)R9、-C(NR9)N(R9)R9、-N(R9)S(O)R9、-S(O)R9、-S(O) OR9、-N(R9)S(O)N(R9)2、-S(O)N(R9)2、-N(R9)S(O)2R9、-S(O)2R9、-S(O)2OR9、-N(R9)S(O)2N (R9)2、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9、-N(R9)C(O)OR9、-N (R9)C(O)N(R9)2、-O(CH2)2-4OR9、-O(CH2)2-4N(R9)2、-O(CH2)2-4N(R9)S(O)2R9、-O(CH2)2-4N(R9)S (O)2N(R9)2、-N(R9)(CH2)2-4OR9、-N(R9)(CH2)2-4N(R9)2、-N(R9)(CH2)2-4N(R9)S(O)2R9Or-N (R9) (CH2)2-4N(R9)S(O)2N(R9)2；
=RA2For=O ,=S ,=N (R9) ,=N (OR9) ,=C (RA3)2,=(C3-6Spiro cycloalkyl group), or=(3- to 6- members Spiro heterocyclic radical), wherein, each RA3It independently is hydrogen, halogen, cyano group, C1-4Alkyl, C3-8Cycloalkyl or 3- are to 8- heterocyclic radicals；Or Two R of personA3Coupled atom is collectively forming C3-6Cycloalkyl or 3- are to 6- circle heterocycles bases；
Each RBIt independently is hydrogen, C1-4Alkyl ,-C (O) R9、-CH2-OP(O)2(OR9)2Or-P (O) (OR9)2；
Each RCIt independently is hydrogen or C1-4Alkyl；
Each above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally and independently of one another Replaced by the 1-3 substituents for being each independently selected from the following group：Halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- is to 12- circle heterocycles base, aryl, heteroaryl ,-CN ,-NO2、-OR9、-SR9、-N(R9)2、-C(O)R9、-C(O)OR9、-C(O)N (R9)2Or-S (O)2R9；
Unless stated otherwise, above-mentioned aryl is the aryl containing 6-12 carbon atom；Heteroaryl is 5- to 15- member heteroaryls Base.
In another preference, the formula (II) of a part for the compound shown in formula (I) is used as
Wherein,
Represent formula (II) and the connection site of the compound remainder shown in formula (I)；
Each R3、R4、R5And R6Each each as described above.
In another preference, formula (II)
Wherein, each R3、R4And R5Each each as described above.
In another preference, in the formula (III) as a part for the compound shown in formula (I),
Wherein,
Formula (III) and the connection site of the compound remainder shown in formula (I) are represented, m and n are respectively each 0；R1、R2And R is each each as described above.
In another preference, formula (III)
Wherein R is as described above.
In another preference, the compound shown in formula (I) is for example shown in formula IV, IV ', IV " or IV " '：
Wherein,
Each R1、R2、R3、R4And R is each each as described above.
In another preference, the compound shown in formula (I) is for example shown in Formula V, V ', V " or V " '：
Wherein,
Each R1、R2、R3、R4And RAEach each as described above.
In another preference, shown in the compound such as formula (VI) shown in formula (I)：
Wherein,
R3For hydrogen, halogen or C1-4Alkyl；
R4For hydrogen, halogen, C1-4Alkyl, C3-8Cycloalkyl, cyano group, OR9；
RAIt is selected from：
Wherein, RA1As described above,Represent RAWith the connection site of the compound remainder shown in formula (VI).
In another preference, RAWith 1-3 (being preferably 1 or 2) RA1Substituted radical, preferably at least described in 1 RA1Substituted radical instead of RAHydrogen on middle tertiary carbon atom.
In another preference, each RAIt independently is
Wherein a, b, c are each independently 0,1,2, or 3；Each RA1As described above,Table Show formula and the connection site of the compound remainder shown in formula (VI).
In another preference, each RAIndependently selected from：
Wherein, RA1As described above.
In another preference, shown in the compound such as formula (VII) shown in formula (I)：
Wherein,
R4For hydrogen, halogen；
RAIt is selected from：
Wherein, RA1For-OR9、-N(R9)2、-NHC(O)R9、-NHC(O)NHR9、-NHS(O)2R9Or-NHS (O)2NHR9、-C (O)N(R9)2、-O(CH2)2-4OR9, wherein, R9For hydrogen, C1-4Alkyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles base, aryl, heteroaryl Base, C3-8Cycloalkyl C1-4Alkyl, 3- are to 8- circle heterocycles bases C1-4Alkyl, aryl C1-4Alkyl or heteroaryl C1-4Alkyl；Or in N (R9)2In structure, two R9Coupled nitrogen-atoms is collectively forming 3- to 8- yuan of rings, and the 3- to 8- yuan of rings optionally also contains There is 0-2 to be independently selected from N, O or S hetero atoms, and the 3- is optionally replaced by=O to 8- yuan of rings；
Represent RAWith the connection site of the compound remainder shown in formula (VII).
In another preference, described formula (I) compound has the structure being selected from the group：
In another preference, described formula (I) compound has the structure being selected from the group：
The second aspect of the present invention is used for there is provided the purposes of the formula described in first aspect present invention (I) compound：
(a) medicine of the treatment disease related to IDO and/or TDO activity or expression is prepared；And/or
(b) IDO and/or TDO targeted inhibition agent is prepared；And/or
(c) suppress IDO and/or TDO activity external non-therapeutic.
In another preference, " IDO and/or the TDO activity or the related disease of expression " include tumour (e.g., lung cancer, Carcinoma of urinary bladder, breast cancer, kidney, stomach cancer, liver cancer, oophoroma, prostate cancer, cervical carcinoma, intestinal cancer, cell carcinoma, multiple bone Myeloma, cancer of pancreas, lymthoma, leukaemia)；Infection (such as virus infection, bacterium infection)；The nervous system disease is (such as depressed, A Er Ci Haimo diseases, multiple sclerosis, parkinsonism, Huntingdon disease etc.)；Atherosclerosis；Inflammation；Pain etc..
There is provided a kind of pharmaceutical composition for the third aspect of the present invention, it is characterised in that described pharmaceutical composition bag Include：(i) compound described in the first aspect present invention of effective dose, or its pharmaceutically acceptable salt；(ii) pharmaceutically may be used The carrier of receiving.
The fourth aspect of the present invention includes step there is provided a kind of method of suppression IDO and/or TDO activity, methods described Suddenly：To suppress object apply suppress effective dose formula (I) compound as described in the first aspect of the invention or its can pharmaceutically connect The salt received, or the pharmaceutical composition as described in third aspect present invention of suppression effective dose is applied to suppressing object.
The fifth aspect of the present invention, should there is provided a kind of preparation method of compound as described in the first aspect of the invention Method includes step：
(a) in atent solvent, compound A1 and compound A2 reactions obtain compound A-13
(b) in atent solvent, compound A-13 and compound A4-1 or compound A4-2 react in the presence of a base Obtain compound A-45
(c) in atent solvent, compound A-45 and acid reaction obtain compound A6
(d) compound A7 is obtained with reducing agent reducing compound A6
Wherein, ring B, R3、R4、R5、RAEach as described above.
In another preference, RAIt is selected from the following group：
Wherein RA1As described above.
Embodiment
The present inventor in-depth study by long-term a, it has unexpectedly been found that class has IDO1 and TDO inhibitory activity Heterocyclic compound, therefore can be used for preparing the drug regimen for treating the disease related to IDO1 and/or TDO activity or expression quantity Thing.Based on above-mentioned discovery, inventor completes the present invention.
Term
Except special instruction part, "or" referred to herein have with "and/or" identical meaning (refer to "or" and " and ").
In place of special instruction, among all compounds of the invention, each asymmetric carbon atom (chiral centre) can be optional Ground be R configurations or S configurations, or R configurations and S configurations mixture.
As used herein, when individually or as other substituent parts, term " alkyl " refers to 1~8 carbon original The straight chain (that is, unbranched) or branched alkyl of son, or its combination.Described alkyl can be saturation, single insatiable hunger and/or it is many not Saturation, and the atomic group of divalence or multivalence can be included.When before alkyl have carbon number limit (such as C1-10) when, refer to described Alkyl contain 1-10 carbon atom, for example, C1-8Alkyl can include the straight or branched alkyl with 1-8 carbon atom, example Such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
As used herein, when individually or as other substituent parts, term " alkenyl " refers to straight or branched, tool There is the carbochain of at least one carbon-carbon double bond.Alkenyl with a double bond can be represented as-CnH2n-1, the alkene with 2 double bonds Base can be represented as-CnH2n-3.When before alkenyl have carbon number limit (such as C2-8) when, refer to described alkenyl and contain 2-8 Carbon atom, for example, the straight or branched alkenyl with 2-8 carbon atom, such as vinyl, acrylic, 1,2- cyclobutenyls, 2,3- Cyclobutenyl, butadienyl or similar group.
As used herein, when individually or as other substituent parts, term " alkynyl " refers to there is at least one The aliphatic hydrocarbon of triple carbon-carbon bonds.Described alkynyl can be straight or branched, or its combination.In some embodiments In, described alkynyl has 2-12 (for example, 2-8,2-6, or 2-4) individual carbon atom.When before alkynyl have carbon number limit (such as C2-8Alkynyl) when, refer to described alkynyl and contain 2-8 carbon atom, for example, term " C2-8Alkynyl " refers to 2~8 carbon atoms Straight or branched alkynyl, such as acetenyl, propinyl, isopropynyl, butynyl, butynyl, secondary butynyl, tertiary butynyl, Or similar group.
As used herein, when individually or as other substituent parts, term " cycloalkyl " refer to it is with saturation or Monocyclic, bicyclic or tricyclic (including and ring, the bridged ring or loop coil) ring system of fractional saturation.Described cycloalkyl can have 3-16 (for example, 3-10, or 5-10) carbon atom.When before some cycloalkyl have carbon number limit (such as C3-10) when, refer to described Cycloalkyl contain 3-10 carbon atom.In some preferred embodiments, term " C3-8Cycloalkyl " refers to 3~8 carbon atoms Saturation or fractional saturation monocyclic or bicyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopenta, suberyl or similar group. The present invention one preferred embodiment in, C6-12Bridge-type bicyclic alkyl (C6-12Bridged bicycloalkyl) include But it is not limited to following group：
As used herein, term " alkoxy " or " alkyl oxy " refer to the alkyl being connected by oxygen atom (for example ,-O- alkane Base), wherein alkyl is as described above.The example of specific alkoxy for example (but being not limited to) methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.Alkoxy can be taken by one or more For base substitution, described substituent such as halogen, amino, cyano group, or hydroxyl.Alkoxy can be straight or branched.Work as alkane Before epoxide there is carbon number to limit (such as C1-8) when, refer to described cycloalkyl and contain 1-8 carbon atom.
As used herein, when individually or as other substituent parts, term " halogen " refers to F, Cl, Br and I.
As used herein, term " alkoxy carbonyl " refer to straight or branched alkyl-oxygen carbonyl fragment (alkoxy -C= O).Alkoxy can have 1-8 carbon atom.When before alkoxy carbonyl have carbon number limit (such as C1-8) when, refer to described alkane The moieties of Epoxide carbonyl contain 1-8 carbon atom, for example, C1-8Alkoxy carbonyl refers to C1-8Alkoxy -C=O- structures Group, such as methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, or similar group.
As used herein, when individually or as other substituent parts, term " aryl " refers to monocyclic, two rings or condensed ring Aromatic series carbon hydrogen group.Described aryl can be substituted or unsubstituted.When before an aryl have carbon number limit (such as C6-12) when, refer to described aryl and contain 6-12 carbon atom.The example of aryl such as (but being not limited to)：Phenyl, biphenyl Base, naphthyl or similar group (each carbon atom therein can arbitrarily be replaced).Described aryl can be free of or comprising One or more identical or different (such as 2,3,4) hetero atoms, the hetero atom can be selected from N, O or S.
As used herein, when individually or as other substituent parts, term " heteroaryl " refers to monocyclic, two rings or thick The aromatic group of ring, the group has specific ring carbons number (for example, C4-10There are 4-10 into ring carbon original Son), and including at least one identical or different hetero atom selected from N, O or S.Each ring atom can arbitrarily be replaced. Described heteroaryl can be 5- to 15- members, with the 1-5 heteroatomic aromatic rings for being each independently selected from N, O or S Base.The example of heteroaryl such as (but being not limited to)：Pyridine, pyrimidine, pyrroles, indazole, indoles, furans, benzofuran, thiophene, Or similar group.
As used herein, when individually or as other substituent parts, term " heterocyclic radical " refers to monocyclic or condensed ring Saturation or fractional saturation substituent, the group have specific ring carbons number (for example, C3-11There is 3-11 cyclization Carbon atom), and including at least one identical or different hetero atom selected from N, O or S.Described heterocyclic radical can be 3- extremely 15- members, with the 1-5 heteroatomic heterocyclic radicals for being each independently selected from N, O or S.The example of heterocyclic radical is for example (but not It is limited to)：Azacyclyl, oxa- ring group, thia ring group, nitrogen oxa- ring group, nitrogen thia ring group, oxygen thia ring group etc., more preferably For the heterocyclic radical appeared in each embodiment of the application.In the present invention, heterocyclic radical can for it is monocyclic, bicyclic or tricyclic (including simultaneously Ring, bridged ring or loop coil).One in the present invention is preferably carried out in mode, the 6- to 12- member bridge-type bicyclic heterocycles bases (Bridged bicyclic heterocyclyl) includes but is not limited to following group：
As used herein, term " arbitrary " or " optionally " (for example, " arbitrarily being replaced "), refer to described part and are It is substituted or unsubstituted, and the substitution only occur with chemically achievable position.For example, H, covalent bond or-C (=O)-base Group cannot be substituted with a substituent.
As used herein, " oxygen " or " epoxide " refers to=O.As used herein, unless stated otherwise, term " can pharmaceutically connect The salt received ", which refers to, to be adapted to contact with the tissue of object (for example, people), the salt of the side effect without producing immoderation.In some realities Apply in example, the pharmaceutically acceptable salt of a certain compound of the invention includes the compound of the invention with acidic-group Salt (for example, sylvite, sodium salt, magnesium salts, calcium salt) or the salt of the compound of the invention with basic group are (for example, sulfate, salt Hydrochlorate, phosphate, nitrate, carbonate).
As used herein, term " substitution " (when being modified with or without " arbitrarily ") refers to one or many on specific group Individual hydrogen atom is replaced by specific substituent.Specific substituent is the substituent accordingly described above, or respectively implemented Substituent appeared in example.Unless stated otherwise, some group arbitrarily replaced can be in any commutable of the group There is a substituent for being selected from specific group, described substituent can be identical or different on each position on site. Cyclic substituents, such as Heterocyclylalkyl, can be connected with another ring, such as cycloalkyl, so that spiral shell second cycle line is formed, for example, Two rings have a shared carbon atom.It will be understood by those skilled in the art that the combination of the substituent desired by the present invention is that Combination stablize a bit or chemically achievable.The substituent such as (but being not limited to)：C1-8Alkyl, C2-8Alkenyl, C2-8Alkynes Base, C3-8Cycloalkyl, 3- are to 12- circle heterocycles bases, aryl, heteroaryl, halogen, hydroxyl, carboxyl (- COOH), C1-8Aldehyde radical, C2-10Acyl Base, C2-10Ester group, amino.
For convenience and meet conventional understanding, term " any substitution " or " optionally substituted " are only applicable to be substituted The site that base is replaced, without including those chemically irrealizable substitutions.
The universal synthesis method of compound
Compound shown in this formula I of the present invention can be made by following method, but the condition of this method, for example, react Thing, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction required time etc. are not limited to following explanation.Chemical combination of the present invention Various synthetic methods describing in this manual or known in the art can also optionally be combined and easily made by thing , such combination can easily be carried out by those skilled in the art in the invention.
In the preparation process in accordance with the present invention, each reaction is generally in atent solvent, and -78 DEG C of reaction temperature~150 DEG C are (preferably 20~120 DEG C) under carry out.Each step reaction time is usually 0.5~48h, preferably 2~12h.
Reaction equation A describes compound A7 universal synthesis method：
Reaction equation A：
Pharmaceutically acceptable salt, solvate, stereoisomer, dynamic isomer
As used herein, term " pharmaceutically acceptable salt " refers to the compounds of this invention and pharmaceutically acceptable inorganic acid The salt formed with organic acid, wherein, inorganic acid preferably includes (but being not limited to)：Hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphur Acid；It is preferred that organic acid include (but being not limited to)：Formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), asiatic acid, Oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethacetic acid, malonic acid, butanedioic acid, fumaric acid, pimelic acid, oneself Diacid, maleic acid, malic acid, sulfamic acid, benzenpropanoic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, to toluene Sulfonic acid, citric acid, and amino acid.
As used herein, term " pharmaceutically acceptable solvate " refer to the compounds of this invention with it is pharmaceutically acceptable Solvent formation solvate, wherein, the pharmaceutically acceptable solvent includes (but being not limited to)：It is water, ethanol, methanol, different Propyl alcohol, tetrahydrofuran, dichloromethane.
As used herein, term " pharmaceutically acceptable stereoisomer " refers to chiral carbon original involved by the compounds of this invention Son can be R configurations, or S configurations, or its combination.
Pharmaceutical composition and application process
Because the compounds of this invention has excellent to IDO1 and TDO inhibitory activity, therefore the compounds of this invention and its each Kind of crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and containing the compounds of this invention be main The pharmaceutical composition of active component can be used for treating, prevent and alleviating by related to IDO1 and/or TDO activity or expression quantity Disease.According to prior art, the compounds of this invention can be used for treating following disease (but being not limited to)：Various cancers, row such as lung It is cancer, carcinoma of urinary bladder, breast cancer, kidney, stomach cancer, liver cancer, oophoroma, prostate cancer, cervical carcinoma, intestinal cancer, cell carcinoma, multiple Myeloma, cancer of pancreas, lymthoma, leukaemia etc.；Infectious disease caused by viral, such as HIV, HPV, the disease caused by virus such as HCV Disease；The nervous system disease, such as depression, Alzheimer disease, multiple sclerosis, parkinsonism, Huntingdon disease；It is dynamic Pulse atherosclerosis, inflammation, pain etc..The pharmaceutical composition of the present invention comprising the compounds of this invention in the range of safe and effective amount or Its pharmacologically acceptable salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " is referred to：Chemical combination The amount of thing is enough to be obviously improved the state of an illness, and is unlikely to produce serious side effect.Generally, pharmaceutical composition contains 1-2000mg sheets Invention compound/agent, more preferably, contains 5-200mg the compounds of this invention/agent.It is preferred that described is " one " for a capsule Or tablet.
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or jello Matter, they are suitable for people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " is referred to herein as combined In thing each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on Plain acetic acid esters of dimension etc.), gelatin, talcum, kollag (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent Wetting agent (such as lauryl sodium sulfate), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application includes (but being not limited to)：Orally, in knurl, rectum, parenteral (intravenous, intramuscular is subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed with least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions are mixed：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) bond Agent, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；(c) NMF, example Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, farina or tapioca, alginic acid, some composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；Lubricant, for example, talcum, calcium stearate, tristearin (i) Sour magnesium, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In capsule, tablet and pill, formulation can also be included Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can using be coated and shell material prepare, such as casing and Other materials well known in the art.They can include reactive compound or compound in opacifying agent, also, this composition Release can discharge in certain part in a delayed fashion in alimentary canal.The example of adoptable embedding component is polymeric material And Wax.If necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can include the inert diluent routinely used in this area, and such as water or other solvents increase Solvent and emulsifying agent, example knows, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3-BDO, dimethyl formyl The mixture of amine and oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these materials Deng.
In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent and suspending agent, sweet taste Agent, flavouring and spices.
Except active ingredient beyond the region of objective existence, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Mixture of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these materials etc..
For parenteral injection composition can comprising physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethanol, polyalcohol and its suitable mixture.
Formulation for the local the compounds of this invention being administered includes ointment, powder, patch, propellant and inhalant. Active component aseptically with physiologically acceptable carrier and any preservative, buffer, or if necessary may need Propellant be mixed together.
The compounds of this invention can be administered alone, or with other pharmaceutically acceptable compound administering drug combinations.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment during using pharmaceutical composition (such as people), wherein dosage is the effective dosage pharmaceutically thought when applying, for the people of 60kg body weight, day is to medicament Amount is usually 1~2000mg, preferably 5~500mg.Certainly, specific dosage be also contemplated that method of administration, patient health situation etc. because Element, within the scope of these are all skilled practitioners technical ability.
Main advantages of the present invention include：
1. there is provided a kind of compound shown in formula I.
2. there is provided a kind of novel IDO1 and/or TDO inhibitor of structure and its preparation and application, described inhibitor exists IDO1 and/or TDO activity can be suppressed under extremely low concentration.
3. treat the pharmaceutical composition with IDO1 and/or TDO activity related diseases there is provided a class.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Embodiment 1：The preparation of compound 1
Under stirring at room temperature by iodomethane (1.5g, 10.57mmol) be added drop-wise in five minutes compound 1a (1.2g, 7.05mmol) with potassium carbonate (1.5g, 10.85mmol) in anhydrous DMF (20mL) solution, reaction is mixed Compound is stirred at room temperature 16 hours, and TLC monitoring reactions are completed, and are added 20 milliliters of water to reaction system, are then used ethyl acetate Extract three times (30mL x 3).Merge organic phase with saturated common salt water washing (30mL), and with anhydrous sodium sulfate drying, filter, Yellow solid compound 1b (1.2g, yield 92%) is obtained after filtrate decompression concentration, without being further purified, is directly used in next Step reaction.1H NMR(DMSO-d6,400MHz):δ4.34(s,1H),3.55(s,3H),1.81-1.75(m,6H),1.53-1.48 (m,6H)。
Compound 1b (1.2g, 6.51mmol) and 2,6- lutidines (2.1g, 19.60mmol) are dissolved in dry N, In dinethylformamide (15mL), be then added dropwise thereto at 0 DEG C tert-butyl group dimethyl silyl triflate (5.2g, 19.67mmol), reaction system is stirred at room temperature overnight.20mL water quenchings are added into system to go out, and are extracted with ethyl acetate three times (30mL x 3).Merge organic phase with saturated common salt water washing (30mL), and with anhydrous sodium sulfate drying, filter, filtrate decompression Residue is obtained after concentration.Residue separates (petrol ether/ethyl acetate=50/1) by silica gel column chromatography and obtains yellow oily Compound 1c (1.5g, yield 77%).1H NMR(CDCl3,400MHz):δ3.62(s,3H),1.90-1.85(m,6H),1.68- 1.62(m,6H),0.82(s,9H),0.04(s,6H).
Dimethyl methyl phosphonate (209mg, 1.68mmol) is dissolved in anhydrous tetrahydro furan (6mL) and -78 DEG C are cooled to, N-BuLi (2.5M hexane solutions, 0.84mL, 2.10mmol) is slowly added dropwise thereto, reaction system stirs 40 at -78 DEG C Minute.Then compound 1c (250mg, 0.84mmol) anhydrous tetrahydrofuran solution (1.0mL) is slowly added dropwise to above-mentioned anti- Answer in system, in -78 DEG C of stirring reactions 2 hours.Reaction system is slowly added into the aqueous ammonium chloride solution of ice (10mL), used Ethyl acetate extracts three times (20mL x 3), and the organic phase of merging uses anhydrous sodium sulfate with saturated common salt water washing (20mL) Dry, filter, yellow oily compound 1d (300mg, yield 92%) is obtained after filtrate decompression concentration, without being further purified, It is directly used in next step reaction.1H NMR(CDCl3,400MHz):δ3.79(s,3H),3.77(s,3H),3.14(s,1H),3.08 (s,1H),1.87-1.81(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.04(s,6H).
Sodium hydride (60%, 62mg, 1.55mmol) is added to the compound 1d (300mg, 0.77mmol) of ice bath cooling Anhydrous tetrahydro furan (6mL) in, reaction system was stirred after 20 minutes at room temperature, was again placed in reaction system cold in ice-water bath To 0 DEG C, compound 1e (332mg, 0.77mmol) slow (in 5 minutes) is added in reaction system, the reaction system is in room The lower stirring of temperature 16 hours.Reaction system is slowly added into the aqueous ammonium chloride solution of ice (20mL), three are extracted with ethyl acetate All over (25mL x 3), the organic phase of merging with saturated common salt water washing (20mL), and with anhydrous sodium sulfate drying, filter, filtrate Residue is obtained after being concentrated under reduced pressure.Residue by silica gel column chromatography separate (petrol ether/ethyl acetate=8/1) obtain yellow consolidate Body compound 1f (400mg, yield 74%).1H NMR(CDCl3,400MHz):δ 7.72 (d, J=12.0Hz, 1H), 7.57 (d, J =8.0Hz, 1H), 7.50 (s, 1H), 7.39-7.26 (m, 10H), 7.20-7.16 (m, 6H), 7.10-6.97 (m, 2H), 6.88 (s,1H).1.84-1.78(m,6H),1.71-1.65(m,6H),0.83(s,9H),0.06(s,6H)。
Compound 1f (400mg, 0.57mmol) is dissolved in methanol/acetic acid (10mL/2.5mL), then reaction system adds Heat was to 60 DEG C of stirring reactions 2 hours.LCMS monitoring reactions are finished, and the reaction system is concentrated under reduced pressure, sodium carbonate is added thereto The aqueous solution (30mL), is extracted with ethyl acetate three times (30mL x 3).The organic phase of merging with saturated common salt water washing (30mL), And with anhydrous sodium sulfate drying, filtering, residue is obtained after filtrate decompression concentration.Residue separates (stone by silica gel column chromatography Oily ether/ethyl acetate=8/1) obtain yellow solid compound 1g (220mg, yield 84%).MS 455.2[M+H]+.
Compound 1g (172mg, 0.375mmol) is dissolved in dichloromethane/trifluoroacetic acid (4mL/1mL), the reactant Tie up to stirring reaction 16 hours at room temperature.Reaction system is concentrated under reduced pressure, and saturated aqueous sodium carbonate is then added thereto (20mL), is extracted with ethyl acetate three times (20mL x 3).Merge organic phase saturated common salt water washing (20mL), anhydrous slufuric acid Sodium is dried, filtering, the residue obtained after concentration.Residue preparation thin plate chromatography (CH2Cl2/ MeOH=15/1) purifying obtain Yellow solid compound 1h (75mg, yield 59%).1H NMR(CDCl3,400MHz):δ7.55(s,1H),7.40-7.28(m, 2H), 7.18 (s, 1H), 6.94 (dd, J=9.2Hz, 8.4Hz, 1H), 5.74 (d, J=9.6Hz, 1H), 3.49 (s, 1H), 3.43 (dd, J=18.8Hz, 2.0Hz, 1H), 2.80 (dd, J=18.4Hz, 10.4Hz, 1H), 1.91-1.82 (m, 6H), 1.72- 1.66(m,6H)；MS 341.2[M+H]+.
By sodium borohydride (16mg, 0.423mmol) stir under be added to ice bath cooling compound 1h (46mg, In methanol (3mL) solution 0.135mmol), then the reactant mixture continues stirring reaction 8 minutes under ice cooling, 4.So Reaction solution is quenched (10mL) with ice-cold saturated ammonium chloride solution afterwards, and ethyl acetate extracts three times (10mL x 3).Merge organic Mutually washed with saturated aqueous common salt (10mL), anhydrous sodium sulfate drying, filtering, filtrate concentrate after crude product by using preparing thin plate layer Analyse (CH2Cl2:MeOH=10:1) purifying obtains compound as white solid 1 (34mg, yield 73%).1(diastereomer is different by H NMR The mixture of structure body, DMSO-d6,400MHz):δ7.97and 7.95(two s,1H),7.47-7.37(m,2H),7.21and 7.17(two s,1H),7.13-7.04(m,1H),5.63-5.57and 5.55-5.50(two m,1H),4.95and 4.51 (two d, J=6.4Hz, 6.4Hz, 1H), 4.17 (s, 1H), 3.18-3.08 (m, 1H), 2.35-2.20 (m, 1H), 1.83- 1.73(m,1H),1.50-1.31(m,12H)；MS 343.2[M+H]+。
Four enantiomters 1-1,1-2,1-3 and 1-4 of compound 1 prepare chromatogram SFC-80 through Waters chiralitys and carried out Split and obtain.Chiral preparatory column condition：CHIRALCEL OJ posts, Daicel, 30x 250mm, 5 μm；Mobile phase:Solvent orange 2 A is two Carbonoxide, cosolvent is that the ethanol of B 15% contains 0.1%DEA；Detection wavelength:272nm；Column temperature:35℃.Chiral analysis column condition： CHIRALCEL OJ posts, Daicel, 4.6x 100mm, 3 μm；Mobile phase:Solvent orange 2 A is carbon dioxide, and cosolvent B is 20% ethanol Containing 0.1%DEA；Detection wavelength:273nm；Column temperature:35℃.
Compound 1-1:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.38-7.29(m,2H),7.20(s,1H), 6.95-6.90 (m, 1H), 5.61 (d, J=8.8Hz, 1H), 3.53 (d, J=10.8Hz, 1H), 2.43-2.33 (m, 1H), 2.10-1.97(m,1H),1.74-1.45(m,12H)；MS 343.2[M+H]+；RT=2.16min.
Compound 1-2:1H NMR(CDCl3,400MHz):δ7.83(s,1H),7.37-7.29(m,2H),7.18(s,1H), 6.96-6.90 (m, 1H), 5.44 (t, J=4.8Hz, 1H), 3.41 (d, J=10.4Hz, 1H), 2.35-2.27 (m, 1H), 2.06-1.97(m,1H),1.74-1.43(m,12H)；MS 343.2[M+H]+；RT=2.89min.
Compound 1-3:1H NMR(CDCl3,400MHz):δ7.86(s,1H),7.39-7.29(m,2H),7.18(s,1H), 6.95-6.90 (m, 1H), 5.44 (t, J=4.8Hz, 1H), 3.42 (d, J=9.6Hz, 1H), 2.35-2.27 (m, 1H), 2.06- 1.97(m,1H),1.76-1.43(m,12H)；MS 343.2[M+H]+；RT=3.31min.
Compound 1-4:1H NMR(CDCl3,400MHz):δ7.82(s,1H),7.39-7.30(m,2H),7.20(s,1H), 6.94 (dd, J=9.2Hz, 8.4Hz, 1H), 5.61 (d, J=8.4Hz, 1H), 3.53 (d, J=10.8Hz, 1H), 2.43-2.33 (m,1H),2.10-1.97(m,1H),1.73-1.46(m,12H)；MS 343.2[M+H]+；RT=4.46min.
Embodiment 2：The preparation of compound 2
Methyl-phosphoric acid dimethyl ester (811mg, 6.54mmol) is dissolved in anhydrous tetrahydro furan (5mL), -78 are subsequently cooled to DEG C, n-BuLi (2.5M hexane solutions, 2.62mL, 6.54mmol) is slowly added dropwise into reaction solution in the state of stirring.Should 2a is added dropwise into reaction system in the state of -78 DEG C and stirring are kept after -78 DEG C of stirring reactions 1 hour for reaction solution Anhydrous tetrahydro furan (2mL) solution of (300mg, 1.64mmol).The reaction solution is in -78 DEG C of stirring reactions 3 hours, LCMS detections Reaction is finished, and is added saturated aqueous ammonium chloride (5mL) and is quenched, then reaction solution is adjusted into pH=1 with 2M HCl, adds acetic acid second Ester (20mL) stirring, point liquid.Aqueous phase is adjusted to pH=9-10 with saturated aqueous sodium carbonate, adds dichloromethane (10mL X 4) extraction Take four times.Organic phase after merging is washed with saturated aqueous common salt (5mL), anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration Light yellow light yellow oil 2b (220mg, yield 49%) is obtained, without being further purified, next step reaction is directly used in.1H NMR(DMSO-d6, 400MHz):δ3.80(s,3H),3.77(s,3H),3.15(s,1H),3.10(s,1H),1.85-1.53 (m,14H)；MS 276.3[M+H]+。
Sodium hydride (60%, 116mg, 2.91mmol) is added to the compound 2b (200mg, 0.73mmol) of ice bath cooling Anhydrous tetrahydro furan (5mL) in, stirring reaction is after 1 hour at 0 DEG C of reaction system, by compound 1e (315mg, 0.73mmol) It is slowly added into reaction system.The reaction system is stirred at room temperature 3 hours.Reaction system is slowly added into the saturation of ice In ammonium chloride solution (10mL), it is extracted with ethyl acetate three times (25mL x 3).The organic phase of merging saturated common salt water washing (20mL), and with anhydrous sodium sulfate drying, filtering, the crude product after filtrate decompression concentration passes through silica gel column chromatography (dichloromethane/first The elution of the mixed solvent of alcohol=5/1) isolate and purify obtained light yellow solid Compound 2c (90mg, yield 21%).582.3[M+ H]+。
Compound 2c (90mg, 0.15mmol) is dissolved in methanol/acetic acid (4mL/1mL), then the reaction solution is heated to 60 DEG C of stirring reactions 2 hours.LCMS monitoring reactions are finished, and the reaction solution is concentrated under reduced pressure, saturated sodium bicarbonate is added thereto The aqueous solution (5mL), is extracted with ethyl acetate three times (10mL x 3).The organic phase of merging with saturated common salt water washing (10mL), And with anhydrous sodium sulfate drying, filtering, residue is obtained after filtrate decompression concentration.Residue is by using preparation thin plate chromatography (CH2Cl2:MeOH=5:1) purifying obtains light yellow solid Compound 2d (33mg, yield 63%).MS 340.2[M+H]+。
Compound 2d (30mg, 0.088mmol) is dissolved in methanol (1mL), then in the state of 0 DEG C is stirred, to this Sodium borohydride (17mg, 0.45mmol) is added in solution.Reaction solution stirring reaction 15 minutes at 0 DEG C.LCMS monitoring reactions Finish, be directly spin-dried for after reaction solution is quenched with saturated aqueous ammonium chloride (3mL), solid is beaten with appropriate methanol, filtering, Filtrate is concentrated to give product as light yellow solid 2 (30mg, yield 99%).MS 342.2[M+H]+。
Embodiment 3：The preparation of compound 3
By compound 2 (27mg, 0.079mmol), sulfonamide (51mg, 0.53mmol) and diisopropylethylamine (68mg, 0.53mmol) it is dissolved in 1,4- dioxane (1mL).Reaction solution stirring reaction at 100 DEG C is concentrated under reduced pressure to give after 6 hours Residue, by prepare thin plate chromatography (petrol ether/ethyl acetate=7/1) purifying obtain compound as white solid 3 (2.74mg, Yield 8.2%).1H NMR (mixture of diastereomer isomers, DMSO-d6,400MHz):δ7.93and 7.91(two s, 1H),7.46-7.37(m,2H),7.19and 7.14(two s,1H),7.12-7.03(m,1H),6.39(s,2H),6.23(s, 1H), 5.62-5.57and 5.55-5.51 (two m, 1H), 4.96and 4.51 (two d, J=6.4Hz, 6.4Hz, 1H), 3.15-3.04(m,1H),2.34-2.20(m,1H),1.83-1.65(m,7H),1.46-1.28(m,6H)；MS 421.2[M+H ]+。
Embodiment 4：The preparation of compound 4
Compound 2b (110mg, 0.40mmol) and triethylamine (121mg, 1.20mmol) are added into dichloromethane (5mL) In, MsCl (69mg, 0.60mmol) is added in the state of being then stirred at room temperature.Reaction 16 is stirred at room temperature in the reaction system After hour, dichloromethane (15mL) and saturated aqueous common salt (10mL) are added into reaction system, organic phase is isolated after stirring, has Machine is mutually washed with saturated aqueous common salt (5mL), anhydrous sodium sulfate drying, filtering, obtains light yellow after filtrate decompression concentration Grease 4a (63mg, yield 45%), without being further purified, is directly used in next step reaction.MS 354.2[M+H]+。
Sodium hydride (60%, 36mg, 0.89mmol) is added to the compound 4a's (63mg, 0.18mmol) of ice bath cooling In anhydrous tetrahydro furan (5mL), reaction system was stirred after 60 minutes at room temperature, reaction system is placed in ice-water bath be cooled to again 0 DEG C, compound 1e (77mg, 0.18mmol) is added in reaction system.Reaction system is stirred at room temperature 3 hours, will be anti- Answer system to be slowly added into the saturated ammonium chloride solution of ice (10mL), be extracted with ethyl acetate three times (10mL x 3).Merge Organic phase with saturated common salt water washing (10mL), and with anhydrous sodium sulfate drying, filtering, remained after filtrate decompression concentration Thing.Residue obtains light yellow solid Compound 4b by preparing thin plate chromatography (petrol ether/ethyl acetate=3/2) purifying (15mg, yield 13%).1H NMR(DMSO-d6,400MHz,):δ7.61-7.54(m,3H),7.45-7.36(m,10H), 7.24-7.05(m,8H),6.96(s,1H),6.90(s,1H),2.93(s,3H),1.83-1.64(m,12H)。
Compound 4b (15mg, 0.02mmol) is dissolved in methanol/acetic acid (4mL/1mL), then the reaction solution is heated to 60 DEG C of stirring reactions 1 hour.LCMS monitoring reactions are finished, and the reaction solution is concentrated under reduced pressure, saturated sodium bicarbonate is added thereto The aqueous solution (10mL), is extracted with ethyl acetate three times (10mL x 3).The organic phase of merging with saturated common salt water washing (10mL), And with anhydrous sodium sulfate drying, filtering, residue is obtained after filtrate decompression concentration.Residue is by preparing thin plate chromatography (acetic acid Ethyl ester) purifying obtain light yellow solid Compound 4c (7.5mg, yield 79%).MS 418.2[M+H]+.
By sodium borohydride (3.4mg, 0.09mmol) stir under be added to ice bath cooling compound 4c (7.5mg, In methanol (3mL) solution 0.02mmol), reactant mixture continues stirring reaction 15 minutes under ice cooling, 4.Then ice is used Cold saturated ammonium chloride solution is quenched (5mL) and is directly spin-dried for afterwards, and solid is beaten with appropriate methanol, filtering, filtrate decompression concentration, Crude product is isolated and purified by preparing rich plate layer chromatography (methylene chloride/methanol=5/1), obtain compound as white solid 4 (6.51mg, Yield 86%).1H NMR (mixture of diastereomer isomers, DMSO-d6,400MHz):δ7.93and 7.91(two s, 1H),7.46-7.37(m,2H),7.19and 7.15(two s,1H),7.12-7.03(m,1H),6.75(s,1H),5.63- 5.57and 5.55-5.50 (two m, 1H), 5.00and 4.56 (two d, J=6.4Hz, 6.4Hz, 1H), 3.17-3.08 (m,1H),2.89(s,3H),2.35-2.20(m,1H),1.83-1.75(m,1H),1.75-1.65(m,6H),1.49-1.31 (m,6H)；MS 420.2[M+H]+.
Embodiment 5：The preparation of compound 5
The iodo- 5- methyl-imidazoles (1.0g, 4.80mmol) of 4- and DIPEA (1.2g, 9.29mmol) is molten In dry DMF (20mL), under stirring into reaction solution add triphenylchloromethane (1.4g, 5.02mmol), reaction 16 hours is stirred at room temperature in reaction system.Reaction solution is poured into water (40mL), stirring, solid analysis Go out, suction filtration, solid is washed twice respectively with water and ether, solid vacuum drying is obtained into compound as white solid 5b, and (1.3g is received Rate 60%).The compound need not be further purified, and be directly used in next step reaction.
By compound 5b (1.2g, 2.67mmol), compound 5c (500mg, 2.94mmol) and seven water potassium phosphates (1.8g, Isosorbide-5-Nitrae-dioxane/water (12mL/2mL) in the mixed solvent 5.32mmol) is dissolved in, Pd (PPh are added3)4(154mg, 0.134mmol).Reaction system is replaced 3 times with argon gas, and reaction system is heated into 90 DEG C stirs 5 hours.Reaction solution is cooled to room Temperature, is then poured into water (20mL), is extracted with ethyl acetate three times (20mL x 3).The organic layer saturated common salt of merging Water washing, then anhydrous sodium sulfate drying, filtering, the crude product obtained after filtrate decompression concentration by column chromatography for separation (petroleum ether/ The purifying of ethyl acetate=5/1) obtains yellow solid compound 5d (440mg, yield 37%).1H NMR(DMSO-d6, 400MHz,):δ9.84(s,1H),7.67-7.61(m,1H),7.50-7.39(m,9H),7.30-7.25(m,3H),7.19- 7.12(m,6H),1.46(s,3H).
Compound 1d (150mg, 0.385mmol) is dissolved in anhydrous tetrahydro furan (5mL), system is placed in ice-water bath It is cooled to 0 DEG C, sodium hydride (60%, 46mg, 1.15mmol) is added into system, stirs 30 minutes at room temperature.Again by reactant System, which is placed in ice-water bath, is cooled to 0 DEG C, and compound 5d (172mg, 0.386mmol) is added in reaction system in three batches.Reaction System was stirred at room temperature after 2 hours, and reaction system is poured slowly into saturated ammonium chloride solution into (20mL), ethyl acetate is used Extract three times (20mL x3).The organic phase of merging saturated common salt water washing (20mL), anhydrous sodium sulfate drying, filtering, filtrate Yellow solid compound 5e is obtained after concentration.The compound is not further purified, and is directly used in next step reaction.
The compound 5e of above-mentioned gained is dissolved in methanol/acetic acid (4mL/1mL), then the reaction solution is heated to 60 DEG C and stirred Mix reaction 2 hours.LCMS monitoring reactions are finished, and the reaction solution is concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution is added thereto (10mL), is extracted with ethyl acetate three times (10mL x 3).The organic phase of merging saturated common salt water washing (10mL), Ran Houwu Aqueous sodium persulfate is dried, filtering, and the crude product obtained after filtrate concentration (is mixed petrol ether/ethyl acetate=2/1 by preparative chromatography thin plate Bonding solvent elute) purifying obtain yellow solid compound 5f (48mg, two step yields 27%).MS 469.3[M+H]+。
Compound 5f (48mg, 0.103mmol) is dissolved in dichloromethane/trifluoroacetic acid (2mL/0.5mL), the reactant Tie up to stirring reaction 5 hours at room temperature.TLC monitoring reactions are finished, and the reaction solution is concentrated under reduced pressure, unsaturated carbonate is added thereto Hydrogen sodium water solution (10mL), is extracted with ethyl acetate three times (10mL x 3).The organic phase of merging saturated common salt water washing (10mL), then anhydrous sodium sulfate drying, filtering, the crude product obtained after filtrate concentration by preparative chromatography thin plate (dichloromethane/ The purifying of methanol=25/1) obtains yellow solid compound 5g (35mg, yield 96%).MS 355.2[M+H]+。
Compound 5g (34mg, 0.096mmol) is dissolved in methanol (1mL), boron hydrogen is then added under 0 DEG C of stirring Change sodium (11mg, 0.289mmol).Reaction system stirring reaction 10 minutes at 0 DEG C.TLC monitoring reactions are finished, by reaction solution It is quenched, is extracted with ethyl acetate three times (5mL x 3) with saturated aqueous ammonium chloride (5mL).The organic phase of merging is eaten with saturation Salt water washing, then anhydrous sodium sulfate drying, is filtered, and the crude product obtained after filtrate concentration passes through preparative chromatography thin plate (dichloromethane The purifying of alkane/methanol=15/1) obtains compound as white solid 5 (32mg, yield 94%).1H NMR be (diastereomer isomers Mixture, DMSO-d6,400MHz):δ7.78(s,1H),7.45-7.35(m,2H),7.08-6.97(m,1H),5.55- 5.51and 5.50-5.41 (two m, 1H), 4.92and 4.48 (two d, J=6.4Hz, 6.4Hz, 1H), 4.15 (s, 1H), 3.16-3.07(m,1H),2.33(s,3H),2.28-2.17(m,1H),1.79-1.69(m,1H),1.50-1.31(m,12H)； MS 357.2[M+H]+。
Embodiment 6：The preparation of compound 6
Compound 6a (1.5g, 6.25mmol) is dissolved in methanol/water (15mL/3mL), hydroxide is then added thereto Potassium (350mg, 6.24mmol), reaction system is stirred at room temperature reaction and stayed overnight.Reaction system is concentrated under reduced pressure removing methanol, addition Water (15mL), is extracted with ethyl acetate twice (15mL x 2).It is 3 that water layer, which is neutralized to pH with watery hydrochloric acid, then uses ethyl acetate Extract three times (15mL x 3).The organic phase of merging is with saturated common salt water washing (20mL), then anhydrous sodium sulfate drying, mistake Filter, yellow solid compound 6b (1.0g, yield 71%) is obtained after filtrate concentration.The compound need not be further purified, directly For next step reaction.1H NMR(DMSO-d6,400MHz):δ12.04(s,1H),3.57(m,3H),1.83-1.62(m, 14H)。
Compound 6b (1.5g, 6.25mmol) is dissolved in acetone (12mL), 1N sodium hydroxides are then added thereto (4.42mL, 4.42mmol) aqueous solution, reaction system is stirred at room temperature 10 minutes, then by silver nitrate (790mg, 4.65mmol) aqueous solution is slowly added dropwise into reaction system.Reaction system is stirred at room temperature 20 minutes, suction filtration, solid water, Acetone, ether are washed successively, and solid vacuum drying is obtained into compound as white solid 6c (1.2g, yield 75%).
Compound 6c (1.2g, 3.60mmol) is scattered in petroleum ether (12mL), then by bromine (596mg, 3.73mmol) it is slowly added dropwise into system, is stirred at room temperature 20 minutes, is then heated to 80 DEG C of stirring reactions 30 minutes.Will Reaction system is filtered, and uses petroleum ether solid, merging filtrate, filtrate washs (10mL), organic layer with 1N sodium hydroxide solutions With anhydrous sodium sulfate drying, filtering obtains yellow oily compound 6d (225mg, yield 24%) after filtrate concentration.The compound It is not further purified, is directly used in next step reaction.1H NMR(DMSO-d6,400MHz):δ3.58(s,3H),2.44-2.37 (m,6H),1.98-1.60(m,8H)；MS 261.0[M+H]+,263.0[M+H]+。
Compound 6d (225mg, 0.86mmol) is dissolved in 1% sodium hydroxide (23mL), reaction system is heated to 100 DEG C stirring 16 hours.Reaction solution is cooled to room temperature, it is 3 that system pH is neutralized to watery hydrochloric acid, is extracted with ethyl acetate seven times (20mL x 7).The organic phase anhydrous sodium sulfate drying of merging, filtering obtains yellow solid compound 6e after filtrate concentration (144mg, yield 90%).The compound need not be further purified, and be directly used in next step reaction.1H NMR(DMSO-d6, 400MHz):δ11.96(s,1H),4.21(s,1H),1.82-1.45(m,14H).
Compound 6e (140mg, 0.76mmol) and potassium carbonate (157mg, 1.14mmol) are dissolved in dry N, N- diformazans In base formamide (2mL), iodomethane (324mg, 2.25mmol) is then added dropwise thereto, it is small that reaction system is stirred at room temperature 16 When.10mL water quenchings are added into system to go out reaction, are extracted with ethyl acetate three times (10mL x 3).The organic phase saturation of merging Brine It (10mL), then with anhydrous sodium sulfate drying, filtering, the crude product obtained after filtrate decompression concentration passes through column chromatography Separation (petrol ether/ethyl acetate=3/1 mixed solvent elution) purifying obtains yellow solid compound 6f (139mg, yield 92%).1H NMR(DMSO-d6,400MHz):δ4.22(s,1H),3.56(s,3H),1.83-1.50(m,14H)；MS 199.2 [M+H]+。
Compound 6f (137mg, 0.69mmol) and 2,6- lutidines (227mg, 2.12mmol) are dissolved in dry In N,N-dimethylformamide (2mL), tert-butyl group dimethyl silyl triflate is then added dropwise thereto at 0 DEG C (559mg, 2.12mmol), reaction system is stirred at room temperature overnight.10mL water quenchings are added into system to go out, and are extracted with ethyl acetate Take three times (10mL x 3).Merge organic phase with saturated common salt water washing (10mL), and with anhydrous sodium sulfate drying, filtering, filter Liquid obtains residue after being concentrated under reduced pressure.By column chromatography for separation, (mixed solvent of petrol ether/ethyl acetate=50/1 drenches residue Wash) purifying obtain yellow solid compound 6g (60mg, yield 28%).1H NMR(CDCl3,400MHz):δ3.65(s,3H), 1.93-1.60(m,14H),0.83(s,9H),0.07(s,6H)。
Dimethyl methyl phosphonate (72mg, 0.58mmol) is dissolved in anhydrous tetrahydro furan (1.5mL) and -78 are cooled to DEG C, n-BuLi (2.5M hexane solutions, 0.31mL, 0.78mmol) is slowly added dropwise thereto, reaction system is in -78 DEG C of stirrings 30 minutes.Then compound 6g (60mg, 0.19mmol) anhydrous tetrahydrofuran solution (0.3mL) is slowly added dropwise to above-mentioned anti- Answer in system, in -78 DEG C of stirring reactions 2 hours.Reaction system is slowly added into the saturated ammonium chloride solution of ice (10mL), It is extracted with ethyl acetate three times (10mL x 3), the organic phase of merging uses anhydrous slufuric acid with saturated common salt water washing (10mL) Sodium is dried, filtering, and the crude product obtained after filtrate concentration obtains yellow solid by column chromatography for separation (ethyl acetate elution) purifying Compound 6h (60mg, yield 77%).1H NMR(CDCl3,400MHz):δ3.80-3.76(m,6H),3.13(s,1H),3.07 (s,1H),1.91-1.58(m,14H),0.84and 0.83(two s,9H),0.07and 0.05(two s,6H)；MS 405.2[M+H]+。
Sodium hydride (60%, 17mg, 0.43mmol) is added to the compound 6h's (60mg, 0.14mmol) of ice bath cooling In anhydrous tetrahydro furan (1.5mL), reaction system was stirred after 30 minutes at room temperature, was again placed in reaction system cold in ice-water bath To 0 DEG C, compound 1e (78mg, 0.18mmol) is slowly added into reaction system, it is small that the reaction system is stirred at room temperature 2 When.Reaction system is slowly added into the saturated ammonium chloride solution of ice (10mL), three times (10mL x are extracted with ethyl acetate 3), the organic phase of merging is with saturated common salt water washing (10mL), and with anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration Obtain residue.Residue obtains yellow solid compound by preparative chromatography thin plate (petrol ether/ethyl acetate=4/1) purifying 6i (20mg, yield 20%).
Compound 6i (20mg, 0.028mmol) is dissolved in methanol/acetic acid (2mL/0.5mL), then the reaction solution is heated To 60 DEG C of stirring reactions 2 hours.LCMS monitoring reactions are finished, and reaction solution is concentrated under reduced pressure, saturated sodium bicarbonate is added thereto The aqueous solution (10mL), is extracted with ethyl acetate three times (10mLx3).The organic phase of merging is with saturated common salt water washing (10mL), so Use anhydrous sodium sulfate drying afterwards, filtering, after filtrate concentration obtained crude product by preparative chromatography thin plate (methylene chloride/methanol= 30/1) purifying obtains yellow solid compound 6j (10mg, yield 76%).MS 469.3[M+H]+。
Compound 6j (10mg, 0.021mmol) is dissolved in dichloromethane/trifluoroacetic acid (1mL/0.25mL), reactant Tie up to stirring reaction 5 hours at room temperature.TLC monitoring reactions are finished, and the reaction solution is concentrated, saturated sodium bicarbonate is added thereto The aqueous solution (5mL), is extracted with ethyl acetate three times (10mL x 3).By the organic phase of merging saturated common salt water washing (10mL), then with anhydrous sodium sulfate drying, filtering, the crude product obtained after filtrate concentration passes through preparative chromatography thin plate (dichloromethane The purifying of alkane/methanol=20/1) obtains yellow solid compound 6k (6mg, yield 79%).MS 355.2[M+H]+。
Compound 6k (6mg, 0.017mmol) is dissolved in methanol (0.5mL), then under 0 DEG C of stirring, to the body Sodium borohydride (2mg, 0.053mmol) is added in system.Reaction solution stirring reaction 10 minutes at 0 DEG C.TLC monitorings have been reacted Finish, reaction solution is quenched with saturated aqueous ammonium chloride (5mL), is extracted with ethyl acetate three times (5mL x 3).By having for merging Machine mutually uses saturated common salt water washing (5mL), then with anhydrous sodium sulfate drying, filtering, the crude product obtained after filtrate decompression concentration Compound as white solid 6 (5.3mg, yield 88%) is obtained by preparative chromatography thin plate (methylene chloride/methanol=12/1) purifying 。1H NMR (mixture of diastereomer isomers, DMSO-d6,400MHz):δ7.93(s,1H),7.48-7.36(m,2H), 7.19and 7.16(two s,1H),7.11-7.02(m,1H),5.62-5.55and 5.53-5.49(two m,1H), 5.04and 4.64 (two d, J=6.0Hz, 6.0Hz, 1H), 4.06 (s, 1H), 3.11-3.04 (m, 1H), 2.33-2.22 (m, 1H),1.83-1.72(m,1H),1.68-1.27(m,14H)；MS 357.2[M+H]+。
Embodiment 7：The preparation of compound 7
Compound 7 is obtained using the preparation method similar to compound 1.1H NMR (mixture of diastereomer isomers, DMSO-d6,400MHz):δ7.95and 7.91(two s,1H),7.46-7.38(m,2H),7.19and 7.16(two s, 1H),7.14-7.04(m,1H),5.67-5.61and 5.60-5.55(two m,1H),5.04-4.99and 4.59-4.55 (two m,1H),4.47-4.43and 4.22-4.18(two m,1H),3.77-3.73and 3.31-3.20(two m,1H), 3.61-3.52and 3.42-3.34(two m,1H),2.37-2.22(m,1H),1.93-1.74(m,3H),1.67-0.94(m, 7H)；MS 317.2[M+H]+。
Embodiment 8：The preparation of compound 8
Compound 8 is obtained using the preparation method similar to compound 1.1H NMR (mixture of diastereomer isomers, DMSO-d6,400MHz):δ7.95(s,1H),7.44-7.38(m,2H),7.15(s,1H),7.10-7.04(m,1H),5.55 (t, J=4.8Hz, 1H), 4.54 (d, J=6.4Hz, 1H), 3.04-2.98 (m, 1H), 2.38-2.31 (m, 1H), 1.91 (s, 3H),1.87-1.77(m,1H),1.68-1.40(m,12H)；MS 353.2[M+H]+.
Embodiment 9:IDO1 albumen zymetology experimental methods
IDO1 external zymetology experiment is carried out in following reaction system：50mM, pH 6.5 MES buffer solutions, 200nM People source IDO1 protease, 150uM L-Trp, 2250units/mL catalases, 20mM vitamin C and sub- with 10uM Methyl blue.Testing compound is configured to 10mM storing liquid with 100%DMSO, MES buffer solutions is reused and is configured to institute Need concentration.The compound for taking 25uL dilutions to finish is added in 96 orifice plates, then adds 25uL 33.68ng/uL IDO1 albumen, Centrifugation 1min is incubated at room temperature 30min after mixing.After compound incubation, 50uL 50mM is added into reaction system, pH's 6.5 The 300uM L-Trps of MES buffers, 4500unites/mL catalase, 20uM methylene blues and 40mM's Vitamin C.40min is reacted at 25 DEG C.With 50uL 30% (w/v) trichloroacetic acid terminating reaction and in being incubated at 60 DEG C 30min, then 2000rpm centrifugations 5min, takes 2% 4- (dimethylamino) benzaldehyde of supernatant and equivalent (to be dissolved in acetic acid In), incubation at room temperature 10min determines OD values at 490nm.
The suppression percentage of compound is calculated by below equation：
Suppression percentage=100- (Sample signal-low control)/(High control-low of compound control)×100。
Wherein High control are that, without compound group, Low control are also without compound without enzyme Group, other are identical with sample.
Compound IC50 Value Data application XLfit4.3.1 statistical softwares analyze, by inhibiting rate percent data relative to The nonlinear regression and fitting curve of compound concentration.
The activity of representative compound is as shown in table 1.IC50 values：A:1-50nM；B:51-100nM；C:101-500nM；D: >501nM。
The IDO1 activity suppressions of table 1
Compound IDO1 suppresses IC50Value
1 30nM
1-1 D
1-2 A
1-3 D
1-4 B
3 A
4 A
6 22nM
7 204nM
8 91nM
Embodiment 10:Detection suppresses the experimental method of IDO1 activity in HEK293T cells
By 5X106HEK293T cells plant in 2 T75 blake bottle and be placed in 37 DEG C, 5%CO2 incubator respectively It is incubated overnight.Mixed liquor A is made in the 0.6ul opti-MEM for containing 1.5ug hIDO1 plasmids and 300ul；18ul liposome Mixed liquor B is made in fugene6 and 300ul opti-MEM, and places 5 minutes at room temperature.Mixed liquid A and mixed liquid B is mixed, in room After the lower placement of temperature 20 minutes, being added to plant has in HEK293T blake bottle, and one bottle is used as control in addition, is placed in 37 DEG C, 5%CO2's It is incubated overnight in incubator.By the HEK293T for having transiently transfected hIDO1 with the density kind of 20000 cell per wells in 96 orifice plates, often Hole 80ul.10 times of 10ul tryptophan is added in cell, negative control hole is not added with tryptophan.Prepared using complete medium Into 10 times of compound solutions (DMSO concentration is 2%), 10ul compound solution is added in cell.Cell plates are placed in 37 DEG C, it is incubated 16 hours in 5%CO2 incubator.80ul supernatants are gone into another 96 orifice plate, 10ul 6.1N trifluoros are added Acetic acid, 50 DEG C are incubated 30 minutes.2800rpm is centrifuged 10 minutes, and transfer 70ul supernatants are into one 96 hole UV plates.Add 70ul 2% (w/v) to dimethylamine phenyl formaldehyde.The light absorption value at 480nM is measured after mixing.100ul CTG reagents are added in cell plates, are mixed Values of chemiluminescence is detected after even 15 minutes.The activity of representative compound is as shown in table 2.IC50 values：A:≤120nM；B:121- 400nM；C:401-1000nM；D:>1000nM.
The HEK293T cytoactives of table 2 suppress
Embodiment 11:TDO2 albumen zymetology experimental methods
TDO2 external zymetology experiment is carried out in following reaction system：50mM, pH 6.5 kaliumphosphate buffer, 200nM people source TDO2 protease, 300uM L-Trp, 0.2mg/mL catalases, 20mM vitamin C and 20uM is sub- Methyl blue.100X to be measured compound is configured to 1mM starting liquid with 100%DMSO, then three times dilute, 8 are prepared altogether Concentration.Take the compound that finishes of 2uL dilutions to add in 96 orifice plates, then added in each hole 100 μ L 400nM TDO2 and 0.4mg/ml catalases.Centrifugation 1min is incubated at room temperature 10min after mixing.After compound incubation, added into reaction system The 100uL 600uM L-Trps that 50mM, pH6.5 kaliumphosphate buffer are prepared, 40uM methylene blues and 40mM vitamin C.Reaction solution reads reading under OD321 data, normal temperature in real time on the instruments of SpectraMax 384 immediately after mixing 30 seconds when A length of 20 minutes.The data of slope are exported from software, the inhibiting rate of compound is converted into further according to slope.
Inhibiting rate=* 100. maximums of (maximum-hole value)/(maximum-minimum value) refer to the hole value for having enzyme to have substrate, Minimum value is the hole value for only having substrate without enzyme.
Compound concentration and inhibiting rate are substituted into formula, the IC50 of compound is fitted with GraphPad Prism5.0 softwares It is worth, specific formula is：Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)
The activity of representative compound is as shown in table 3.IC50 values：A:1-50nM；B:51-100nM；C:101-500nM；D: >501nM。
The TDO2 activity suppressions of table 3
Compound TDO2 suppresses IC50Value
1 C

Claims (12)

1. a kind of compound as shown in formula (I), or its pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or Solvate：
In formula (I)：
Ring A is 5- member aromatic rings, and wherein each T and U is each independently N or C；Each P, V and W are each independently N or CR3；
Ring B is 5- members or 6- member aromatic rings, and wherein each D, E and F is each independently CR4=CR5、CR4, N, O, S or NR6；
Z is CR8Or N；
R1And R2It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles Base ,-CN ,-OR9Or-N (R9)2；
Or R1And R2Coupled carbon atom is collectively forming optionally containing the 0-2 heteroatomic 3- for being independently selected from N, O or S To 8- yuan of rings；
M and n are each independently 0,1,2,3 or 4；
Each R3It independently is hydrogen, halogen or C1-4Alkyl；
Each R4And R5It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are miscellaneous to 8- members Ring group, aryl, heteroaryl, cyano group, nitro ,-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O)N(R9)2、-C(O)R9、-S(O)2R9、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9Or-N (R9)C(O)N(R9)2；
Each R6It independently is hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles base, aryl, miscellaneous Aryl ,-C (O) R9、-C(O)OR9、-C(O)N(R9)2Or-S (O)2R9；
Each R8It independently is hydrogen, halogen or C1-4Alkyl；
Each R9It is each independently hydrogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles base, virtue Base, heteroaryl, C3-8Cycloalkyl C1-4Alkyl, 3- are to 8- circle heterocycles bases C1-4Alkyl, aryl C1-4Alkyl or heteroaryl C1-4Alkyl；
Or in N (R9)2In structure, two R9Coupled nitrogen-atoms is collectively forming 3- to 8- yuan of rings, the 3- to 8- yuan of rings Optionally also it is independently selected from N, O or S hetero atoms containing 0-2, and the 3- is optionally replaced by=O to 8- yuan of rings；
R is RA、-ORA、-N(RA)(RC)、-C(O)RA、-C(O)N(RA)(RC)、-C(ORB)(RA)(RC)、-C(NHRB)(RA) (RC) ,-C (=N-ORC)RAOr-N (ORC)(RA), wherein,
Each RAIt independently is C6-12Bridge-type bicyclic alkyl (C6-12Bridged bicycloalkyl) or C4-11It is miscellaneous containing 1-3 The 6- of atom is to 12- member bridge-type bicyclic heterocycles base (Bridged bicyclic heterocyclyl)；Each hetero atom is independently selected From N, O or S,
Wherein, RAOptionally there is 1-3 RA1Substituted radical and/or optionally there is 1-2=RA2Substituted radical；
Each RA1It is each independently hydrogen, halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, aryl, heteroaryl, C3-8Cycloalkyl, C3-8Cycloalkenyl group, 3- are to 8- circle heterocycles base, cyano group, nitro, N- oxides ,-OR9、-N(R9)2、-SR9、-C(O)OR9、-C(O)N (R9)2、-C(O)N(OH)R9、-C(O)R9、-C(NR9)R9、-C(NR9)N(R9)R9、-N(R9)S(O)R9、-S(O)R9、-S(O) OR9、-N(R9)S(O)N(R9)2、-S(O)N(R9)2、-N(R9)S(O)2R9、-S(O)2R9、-S(O)2OR9、-N(R9)S(O)2N (R9)2、-S(O)2N(R9)2、-OC(O)R9、-OC(O)OR9、-OC(O)N(R9)2、-N(R9)C(O)R9、-N(R9)C(O)OR9、-N (R9)C(O)N(R9)2、-O(CH2)2-4OR9、-O(CH2)2-4N(R9)2、-O(CH2)2-4N(R9)S(O)2R9、-O(CH2)2-4N(R9)S (O)2N(R9)2、-N(R9)(CH2)2-4OR9、-N(R9)(CH2)2-4N(R9)2、-N(R9)(CH2)2-4N(R9)S(O)2R9Or-N (R9) (CH2)2-4N(R9)S(O)2N(R9)2；
=RA2For=O ,=S ,=N (R9) ,=N (OR9) ,=C (RA3)2,=(C3-6Spiro cycloalkyl group), or=(3- is miscellaneous to 6- member spiral shells Ring group), wherein, each RA3It independently is hydrogen, halogen, cyano group, C1-4Alkyl, C3-8Cycloalkyl or 3- are to 8- heterocyclic radicals；Or two Individual RA3Coupled atom is collectively forming C3-6Cycloalkyl or 3- are to 6- circle heterocycles bases；
Each RBIt independently is hydrogen, C1-4Alkyl ,-C (O) R9、-CH2-OP(O)2(OR9)2Or-P (O) (OR9)2；
Each RCIt independently is hydrogen or C1-4Alkyl；
Each above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are optionally and independently of one another by 1- 3 substituents for being each independently selected from the following group replace：Halogen, C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl, C3-8Cycloalkyl, 3- are extremely 12- circle heterocycles base, aryl, heteroaryl ,-CN ,-NO2、-OR9、-SR9、-N(R9)2、-C(O)R9、-C(O)OR9、-C(O)N(R9)2 Or-S (O)2R9；
Unless stated otherwise, above-mentioned aryl is the aryl containing 6-12 carbon atom；Heteroaryl is 5- to 15- unit's heteroaryls.
2. compound as claimed in claim 1, it is characterised in that be used as the formula of a part for the compound shown in formula (I) (II)
For
Wherein,
Represent formula (II) and the connection site of the compound remainder shown in formula (I)；
Each R3、R4、R5And R6Each each as described above；
Preferably, formula (II)
For
Wherein, each R3、R4And R5Each each as described above.
3. the compound as described in claim 1 to 2, it is characterised in that be used as the formula of a part for the compound shown in formula (I) (III) in,
Wherein,
Formula (III) and the connection site of the compound remainder shown in formula (I) are represented,
M and n are respectively each 0；R1、R2And R is each each as described above；
Preferably, formula (III)
For
Wherein R is as described above.
4. the compound as described in claims 1 to 3, it is characterised in that compound shown in formula (I) for example formula IV, IV ', IV ", Or shown in IV " '：
Wherein,
Each R1、R2、R3、R4And R is each each as described above；
Preferably,
Compound shown in formula (I) is for example shown in Formula V, V ', V " or V " '：
Wherein,
Each R1、R2、R3、R4And RAEach each as described above；
It is highly preferred that
Shown in compound such as formula (VI) shown in formula (I)：
Wherein,
R3For hydrogen, halogen or C1-4Alkyl；
R4For hydrogen, halogen, C1-4Alkyl, C3-8Cycloalkyl, cyano group, OR9；
RAIt is selected from：
Q=0,1,2,3
Wherein, RA1As described above,Represent RAWith the connection site of the compound remainder shown in formula (VI).
5. the compound as described in Claims 1-4, it is characterised in that each RAIt independently is
Wherein a, b, c are each independently 0,1,2, or 3；
Preferably, each RAIt independently is：
Wherein, each RA1As described above,The connection site of expression and the compound remainder shown in formula (VI).
6. compound as claimed in claim 1, it is characterised in that shown in the compound such as formula (VII) shown in formula (I)：
Wherein,
R4For hydrogen, halogen；
RAIt is selected from：
Wherein, RA1For-OR9、-N(R9)2、-NHC(O)R9、-NHC(O)NHR9、-NHS(O)2R9Or-NHS (O)2NHR9、-C(O)N (R9)2、-O(CH2)2-4OR9, wherein, R9For hydrogen, C1-4Alkyl, C3-8Cycloalkyl, 3- are to 8- circle heterocycles base, aryl, heteroaryl, C3-8 Cycloalkyl C1-4Alkyl, 3- are to 8- circle heterocycles bases C1-4Alkyl, aryl C1-4Alkyl or heteroaryl C1-4Alkyl；Or in N (R9)2Knot In structure, two R9Coupled nitrogen-atoms is collectively forming 3- to 8- yuan of rings, and the 3- to 8- yuan of rings is optionally also containing 0-2 It is independently selected from N, O or S hetero atom, and the 3- is optionally replaced by=O to 8- yuan of rings；
Represent RAWith the connection site of the compound remainder shown in formula (VII).
7. compound as claimed in claim 1, it is characterised in that described formula (I) compound has the structure being selected from the group：
8. compound as claimed in claim 1, it is characterised in that described formula (I) compound has the structure being selected from the group：
9. the purposes of formula (I) compound described in claim 1, it is characterised in that be used for：
(a) medicine of the treatment disease related to IDO and/or TDO activity or expression is prepared；And/or
(b) IDO and/or TDO targeted inhibition agent is prepared；And/or
(c) suppress IDO and/or TDO activity external non-therapeutic.
10. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes：(i) claim 1 institute of effective dose The compound stated, or its pharmaceutically acceptable salt；(ii) pharmaceutically acceptable carrier.
11. a kind of method of suppression IDO and/or TDO activity, methods described includes step：Suppression is applied to suppressing object effectively Formula as claimed in claim 1 (I) compound or its pharmaceutically acceptable salt of amount, or apply suppression effectively to suppressing object The pharmaceutical composition as claimed in claim 10 of amount.
12. the preparation method of compound as claimed in claim 1, it is characterised in that the method comprising the steps of：
(a) in atent solvent, compound A1 and compound A2 reactions obtain compound A-13
(b) in atent solvent, compound A-13 and compound A4-1 or compound A4-2 react obtain in the presence of a base Compound A-45
(c) in atent solvent, compound A-45 and acid reaction obtain compound A6
(d) compound A7 is obtained with reducing agent reducing compound A6
Wherein, ring B, R3、R4、R5、RAEach as described above.
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CN108026098A (en) * 2015-04-12 2018-05-11 杭州英创医药科技有限公司 Heterocyclic compound as IDO and TDO inhibitor

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CN103547579A (en) * 2011-04-15 2014-01-29 新联基因公司 Fused imidazole derivatives useful as ido inhibitors
CN105189466A (en) * 2013-03-14 2015-12-23 新联基因公司 Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization
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CN107488179A (en) * 2016-06-11 2017-12-19 鲁南制药集团股份有限公司 Imidazoles 01 derivatives containing bridged ring
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